Process for preparing substituted 1,3-dihydrospiro[benzo(c)thiophene]s

ABSTRACT

Novel substituted 1,3-dihydrospiro[benzo(c)thiophene]s and methods of preparing the same are described. These compounds are useful as antidepressants and tranquilizers and intermediates therefor.

This is a division of application Ser. No. 313,169 filed Oct. 20, 1981now U.S. Pat. No. 4,409,229, which is a continuation-in-part of Ser. No.165,344, filed 7/2/80, now abandoned, which is a continuation of Ser.No. 948,908 filed 10/5/78 now abandoned, which in turn is acontinuation-in-part of Ser. No. 857,177 filed 12/2/77, now abandoned.

This invention relates to novel substituted1,3-dihydrospiro[benzo(c)thiophene]s which are useful asantidepressants, tranquilizers, and as intermediates therefor, tomethods of preparing the same, to methods of treatment withpharmaceutically effective amounts thereof, and to pharmaceuticalcompositions containing such compounds as essential active ingredients.

To the best of our knowledge, the compounds of this invention have notheretofore been described or suggested. Substituted1,3-dihydrospiro[isobenzofuran]s of the formula ##STR1## in which R ishydrogen, alkyl, alkoxy, trifluoromethyl, halogen, hydroxy ormethylenedioxy; R¹ is hydrogen, alkyl, cycloalkylalkyl, alkenyl,phenylalkyl, diphenylalkyl, diphenylmethoxyalkyl, alkanoyl,phenylalkanoyl, benzoyl, benzoylalkyl, phenylhydroxyalkyl,alkoxycarbonyl, phenyloxycarbonyl or cycloalkylcarbonyl; R² is alkyl orphenyl; Y is hydrogen, alkyl, alkoxy, hydroxy, m, n and n' are integersfrom 1 to 3; as well as the optical antipodes and pharmaceuticallyacceptable acid addition salts thereof, are described by Victor J. Baueret al. in U.S. Pat. No. 3,959,475 granted May 25, 1976. Similarly,Marxer et al. in "Spiro Piperidines. I. Synthesis ofSpiro[isobenzofuran-1(3H),4'-piperidines] andSpiro[isobenzofuran-1(3H),3'-piperidines], "J. Org. Chem. Vol. 40, No.10 (1975), describes various isobenzofurans depicted by the formulae:##STR2## in which X is hydrogen, halogen or methoxy, R is methyl orbenzyl, R' is phenyl, substituted phenyl, alkyl, phenylalkyl,diphenylalkyl or thienyl and R" is alkyl, phenyl, benzyl,3-methyl-5-isoxazolyl or pyridyl. However, in this article nopharmaceutical activity is described for the disclosed isobenzofurans.

Neither of these two references describes or suggests the instantlyclaimed compounds. Each discloses isobenzofurans, notbenzo(c)thiophenes. Also, the compounds of this invention cannot beprepared by the syntheses described in the above-mentioned prior art.

This invention relates to novel substituted1,3-dihydrospiro[benzo(c)thiophene]s of the formula: ##STR3## and to theoptical antipodes and pharmaceutically acceptable salts thereof, inwhich R is hydrogen, hydroxy, benzoyloxy, loweralkyl,cycloalkylloweralkyl or cycloalkylloweralkanoyl in which the cycloalkylportion contains from 3 to 6 carbon atoms, loweralkenyl, phenylalkyl,diphenylalkyl, diphenylmethoxyalkyl, phenoxyalkyl, loweralkanoyl,phenylalkanoyl, benzoyl, benzoylalkyl of the formula (CH₂)_(m) COPhR¹R², phenylhydroxyalkyl, alkyloxycarbonyl of 2 to 6 carbon atoms,phenyloxycarbonyl, cycloalkylcarbonyl of 4 to 8 carbon atoms or ##STR4##in which Ph is phenyl; R¹ and R² are the same or different and each canbe hydrogen, loweralkyl, loweralkoxy, trifluoromethyl, halogen, hydroxy,methylenedioxy or loweralkylthio m, n and n' are integers from 1 to 3;and the sum of n and n' is 3 or 4. In the above, the modifier "lower"means up to 6 carbon atoms.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acids.

Some compounds within the scope of this invention have greaterpharmaceutical activity than others. The latter compounds arenevertheless desirable and useful as intermediates in the preparation ofthe more active compounds. Preferred compounds are those in which R ishydrogen, alkyl of 1 to 3 carbon atoms, especially methyl, orsubstituted benzoylpropyl with optimum compounds being further limitedin that the n and n' are both 2.

The compounds of the invention may be prepared by any of several methodsof preparation described below. In this description, R, R¹, R², n, n'and m are, with the exceptions noted as defined previously.

METHOD A

A 2-bromofluorobenzene (I) wherein R¹ is not hydroxy, is converted toits lithio derivative (II) by any convenient method, e.g., by reactionwith a loweralkyllithium at a temperature from -100° to -50° C. in asolvent such as ether, hexane or tetrahydrofuran. A preferred methodinvolves reaction with butyllithium in tetrahydrofuran at a temperaturebetween -70° and -60° C. ##STR5##

The resulting 2-lithio derivative is reacted with a cycloazalkanone ofthe formula ##STR6## wherein R is alkyl or phenylalkyl under reactionconditions which are commonly used for this type of reaction, e.g., at atemperature of -80° to -20° C., preferably -80° to -40° C., in a solventsuch as ether, tetrahydrofuran or hexane to provide aphenylcycloazalkanol (III). ##STR7##

The phenylcycloazalkanol (III) is treated with a benzylmercaptan of theformula ##STR8## and a Lewis Acid such as titanium tetrachloride orboron trifluoride etherate at a temperature of from ambient to 100° C.to provide the corresponding benzylthiophenylcycloazalkane (IV).##STR9##

The benzylthiophenylcycloazalkane is cyclized to provide thecorresponding 1,3-dihydrospiro[benzo(c)thiophene-cycloazalkane] (V), acompound of the invention ##STR10##

A preferred method includes the use of sodium hydride as acondensing/cyclization agent with a solvent such as dimethylsulfoxide ata temperature of from 25° to 100° C.

METHOD B

A 1,3-dihydrospiro[benzo(c)thiophene-cycloazalkane] (V) prepared inMethod A, is treated with a chloroformate, e.g., an alkyl- or phenylchloroformate, at a temperature of from 15° to 125° C., in a solventsuch as toluene, benzene or methylene chloride with or without an acidscavenger such as sodium bicarbonate, to provide the correspondingN-alkoxycarbonyl- orN-phenoxycarbonyl-1,3-dihydrospiro[benzo(c)thiophene-cycloazalkane](VI), a compound of the invention, in which R³ is lower alkyl or phenyl.##STR11##

METHOD C

A compound of the invention prepared in Method B is treated with a basesuch as sodium or potassium hydroxide in a solvent such as water,ethanol or ethylene glycol at a temperature of from 15° C. to the refluxtemperature of the reaction mixture or with an acid such as hydrogenbromide in acetic acid at a temperature of from 15° to 125° C. toprovide the correspondingN-unsubstituted-1,3-dihydrospiro[benzo(c)thiophene-cycloazalkane],(VII), a compound of the invention. ##STR12##

METHOD D

A compound of the invention prepared in Method C can be treated with acompound of the formula ##STR13## in which R¹ is as defined initially,under normal reaction conditions to provide the corresponding compoundof the invention, (VIII). ##STR14## A preferred method includes the useof potassium iodide as a reaction initiator, sodium bicarbonate as anacid scavenger and dimethylformamide as a solvent at a reactiontemperature of about 75° C.

METHOD E

The compound prepared in Method D is subjected to hydrolysis to providethe corresponding compound of the invention in which R is ##STR15##wherein m and R¹,R² are as defined initially. A preferred methodinvolves the use of a strong acid such as 3N HCl in a solvent such aswater or ethanol.

METHOD F

An N-unsubstituted-1,3-dihydrospiro[benzo(c)thiophene-cycloazalkane](VII) prepared in Method C can be reacted in a known manner with analkanoyl chloride or anhydride, benzoyl chloride or anhyride, aralkanoylchloride, alkyl halide, alkenyl halide, cycloalkanoyl halide or aralkylhalide to provide the corresponding compound of the invention in which Ris alkanoyl, benzoyl, phenylalkanoyl, alkyl, alkenyl,cycloalkylcarbonyl, phenylalkyl or cycloalkylalkyl.

METHOD G

A compound prepared in Method B, E or F in which R is alkoxycarbonyl,phenoxycarbonyl, alkanoyl, benzoyl, phenylalkanoy cycloalkylcarbonyl orbenzoylalkyl can be reduced in a known manner with a reagent such alithium aluminum hydride or diborane to the corresponding compound ifthe invention in which R is alkyl, cycloalkyl, phenylalkyl orphenylhydroxyalkyl.

METHOD H

A compound of the invention prepared in Method C can be treated with aperoxide of the formula ##STR16## in which R¹ is as defined initially,under normal reaction conditions to provide the coresponding compound ofthe invention (I) ##STR17## A preferred method includes the use ofsodium carbonate, benzene solvent and a temperature of about 65°-70° C.

METHOD I

A compound of the invention prepared in Method H can be treated with abase, such as NaOH, under normal hydrolyzing conditions, to provide thecorresponding compound of the invention (X). ##STR18##

METHOD J

A compound of the invention prepared in Method A, B, C, E, F, G, H or Iwhich contains an alkoxy group on a phenyl ring can be heated with anacid, such as hydrobromic acid or aluminum tribromide, under the normalconditions of hydrolyzing reactions to provide the corresponding hydroxy(phenolic) compound, a compound of the present invention.

The compounds of the present invention ae useful in the treatment ofdepression in mammals, as demonstrated by their ability to inhibittetrabenazine-induced depression in mice [International Journal ofNeuropharmacology, 8, 73 (1969)], a standard assay for usefulantidepressant properties. Thus, at intraperitoneal doses of 1.1 and 2.5mg/kgs, respectively,1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine] and1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]effect a 50% inhibition of the ptosis of tetrabenazine-induceddepression in mice. These data illustrate that the compounds are usefulas antidepressants in mammals when administered in amounts ranging from0.1 to 50 mg/kg of body weight per day.

Compounds of the present invention are further useful as tranquilizersdue to their depressant action on the central nervous system of mammals.This ability is demonstrated in the Sidman Avoidance Paradigm [Science,118, 157-8 (1953)], a standard assay for tranquilizers, according towhich compounds of the present invention are shown useful astranquilizers when administered in amounts ranging from 0.1 to about 50mg/kg per day.

The spiro[benzo(c)thiophene-piperidine]s of the present inventiongenerally exhibit minimal or are devoid of anticholinergic activity asdemonstrated by their ability to protect mice against the lethal effectsof physostigmine in a standard assay such as the one described inExample 68.

Other compounds of the invention include:

1,3-dihydro-1'-ethoxycarbonyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-1'-[(3-hydroxy-3-phenyl)propyl]-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

1'-[4-(4-fluorophenyl)-4-hydroxybutyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

1'-cyclohexylmethyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-1'-diphenylmethoxyethyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine);

1'-allyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-1'-methyl-3-(4-methoxyphenyl)spiro[benzo(c)thiophene-1,4'-piperidine];

6-fluoro-3-(4-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-3-(4-methoxyphenyl)spiro[benzo(c)thiophene-1,4'-piperidine];

1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(4-methoxyphenyl)spiro[benzo(c)thiophene-1,4'-piperidine];

6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

4,6-difluoro-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

6-fluoro-1'-[3-(4-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-1'-(4,4-diphenylbutyl)-3-(4-trifluoromethylphenyl)-spiro[benzo(c)thiophene-1,4'-piperidine];

3-(3-bromophenyl)-1,3-dihydro-1'-(3-phenoxypropyl)spiro[benzo(c)thiophene-1,4'-piperidine];

1'-benzoyl-1,3-dihydro-3-(4-hydroxyphenyl)spiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-3-phenyl-1'-phenylacetylspiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-3-(3,4-methylenedioxyphenyl)-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-1'-hydroxy-3-(4-methoxyphenyl)spiro[benzo(c)thiophene-1,4'-piperidine];

3-(3,4-dichlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,3'-pyrrolidine];

1,3-dihydro-1'-methyl-3-(2-methylthiophenyl)spiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-1'-methyl-6-methyltho-3-phenylspiro[benzo(c)thiophene-1,3'-pyrrolidine];

1'-cyclopropylacetyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

6-methyl-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

7-methoxy-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

5-trifluoromethyl-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

4-hydroxy-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

5,6-methylenedioxy-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

1,3-dihydro-1'-methyl-3-(2-methoxyphenyl)spiro[benzo(c)thiophene-1,4'-piperidine];

1'-benzoylpropyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];

1'-benzoylpropyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal;

1'-(4-fluorophenethyl)-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine];and

1,3-dihydro-1'-(3,4-dimethoxyphenyl)propyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Effective quantities of the compounds of the invention may beadministered to a patient by any one of various mehods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable addition salts for purposes of stability,convenience of crystallization, increased solubility and the like.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as microcrystalline cellulose, gumtragacanth or gelatin; and excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, corn starch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus, tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes and colorings and flavors. Materials used inpreparing these various compositions should be pharmaceutically pure andnon-toxic in the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain a pharmaceuticallyeffective amount, i.e., at least 0.1% of active compound, but may bevaried to be between 0.5 and about 30% of the weight thereof. The amountof active compound in such compositions is such that a suitable dosagewill be obtained. Preferred compositions and preparations according tothe present invention are prepared so that a parenteral dosage unitcontains between 0.5 to 100 milligrams of active compound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral preparationcan be enclosed in ampuls, disposable syringes or multiple dose vialsmade of glass or plastic.

The invention is further illustrated by the following examples.

EXAMPLE 1

a. 46 ml of 2.4M n-butyllithium are added over a 15 minute span to amixture cooled to -70° C. of 17.5 g of 2-bromofluorobenzene and 50 ml oftetrahydrofuran. After total addition, the reaction mixture is stirredat between -60° to -70° C. for 15 minutes to enable complete lithiation,which results in a tan colored solution. A mixture of 11.3 g of1-methyl-4-piperidone in 20 ml of tetrahydrofuran is added to thesolution at a rate to maintain the reaction medium's temperature below-60° C. After total addition, the reaction mixture is stirred at thesame low temperature for one hour before being permitted to warm toambient temperature. Water is added and the biphasic mixture ispermitted to separate into its organic and aqueous phases. The organicphase is collected and the aqueous phase is extracted thrice with etherand the ether extracts are combined with the organic phase. The combinedorganic solution is extracted with an excess of 2N hydrochloric acid andthen discarded. The acidic solution is basified with ammonium hydroxide,producing a heavy oil which is dissolved in a 1:1 ethyl acetate ethermixture. This solution is dried and then concentrated to dryness,leaving a viscous oil which crystallizes with cooling. The solid productis recrystallized from a benzene-hexane mixture to give prisms, mp127°-129° C. of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine.

b. A reaction mixture of 4.5 g of4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine, 8 ml of benzylmercaptan, 10 ml of boron trifluoride etherate and 10 ml of glacialacetic acid is stirred at 65° C. for 16 hours. The excess reagents areremoved at 70° C. in vacuo and the residue is taken up with a 1:1ether-2N hydrochloric acid mixture and then permitted to stand at alowered temperature for two hours. The cooled mixture is filtered tocollect its crystalline product. The product is recrystallized from anacetone-ether mixture to give colorless prisms, mp 182°-184° C. of4-benzylthio-4-(2-fluorophenyl)1-methylpiperidine hydrochloride.

c. A mixture of 0.9 g of 50% sodium hydride in 20 ml ofdimethylsulfoxide is heated at 80°-85° C. in a nitrogen atmosphere for30 minutes to produce a solution of sodium methylsulfinylmethide. Thissolution is permitted to cool to ambient temperature. A solution of 4.9g of 4-benzylthio-4-(2-fluorophenyl)-1-methylpiperidine, free base of b,in 10 ml of dimethylsulfoxide is added over a 5 minute span. After totaladdition, the mixture is stirred at ambient temperature for one hour andthen poured onto ice-water. The resulting solid, collected byfiltration, is recrystallized from an ether-hexane mixture to givecolorless prisms, mp 120°-121° C., of1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₁₉ H₂₁ NS: 77.24%C; 7.17%H; 4.74%N; 10.85%S.Found: 77.31%C; 7.20%H; 4.59%N; 10.71%S.

d. With the substitution of 1-methyl-3-pyrrolidone for1-methyl-4-piperidone into the manipulative procedure of Method A,3-(2-fluorophenyl)-3-hydroxy-1-methylpyrrolidine may be obtained.

e. Starting with 3-(2-fluorophenyl(-3-hydroxy-1-methylpyrrolidine, themanipulative procedures of Method A may be implemented to provide1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,3'-pyrrolidine].

f. The substitution of 1-benzyl-3-pyrrolidone for 1-methyl-3-pyrrolidoneinto the manipulative procedures of Example 1d and 1e may provide1'-benzyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,3'-pyrrolidine].

g. With the substitution of 1-methyl-3-piperidone for1-methyl-4-piperidone into the manipulative procedure of Example 1a,3-(2-fluorophenyl)-3-hydroxy-1-methylpiperidine may be obtained.

h. Starting with 3-(2-fluorophenyl)-3-hydroxy-1-methylpiperidine, themanipulative procedures of Example 1b and 1c may be implemented toprovide1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,3'-piperidine].

EXAMPLE 2

a. 9.9 ml (11.9 g) of 4-chlorobenzyl mercaptan and 11.1 ml of borontrifluoride etherate are added sequentially to 5.00 g of4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine. Example 1a, in 11.1 mlof glacial acetic acid. The reaction is stirred at 55°-60° C. for 48hours. The excess reagents are removed at 80° C. in vacuo and theresidue is taken up with a 1:1 ether-2N hydrochloride acid mixture. Thisbiphasic mixture is stirred for 2.5 hours and then for an additional tenminutes after 50 ml of ice are added. The ether layer is decanted off.The aqueous layer is sequentially washed with ether and filtered tocollect a crude product. The product is washed with a small portion ofwater and then a large portion of ether to give a white powder. Thepowder is recrystallized from acetone to give white crystals, mp164°-166° C. of 4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine hydrochloride.

Analysis: Calculated for C₁₉ H₂₁ NClFS.HCl: 59.08%C; 5.74%H; 3.63%N;4.92%F. Found: 59.04%C; 5.56%H; 3.68%N; 4.78%F.

b. A solution of sodium methylsulfinylmethide is produced from 0.7 g of(50%) sodium hydride and 15 ml of dimethylsulfoxide as in Example 1c. Asolution of 4.2 g of4-(4-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine, free baseof a, in 15 ml of dimethylsulfoxide is added to this solution over athree minute span. After total addition, the mixture is stirred atambient temperature for one hour and then poured onto 70 ml ofice-water. The mixture is diluted with water to 120 ml total volumebefore being filtered to collect the crude product. The product iswashed with water and then dissolved with ether. The ethereal solutionis sequentially washed thrice with water and once with a saturatedsodium chloride solution and dried to give yellow-white crystals. Thecrystals are chromatographed with ether through an alumina column togive white crystals, mp 121°-123° C. of3-(4-chlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₁₉ H₂₀ ClNS: 69.19%C; 6.11%H; 4.25%N;10.75%Cl. Found: 69.24%C; 6.21%H; 3.96%N; 10.74%Cl.

EXAMPLE 3

A mixture of 2.3 g of1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine],Example 1, 1.4 g of phenyl chloroformate and 0.5 g of sodium bicarbonatein 40 ml of methylene chloride is stirred at ambient temperature for 4hours before being filtered. The filtrate is sequentially washed with adilute sodium hydroxide solution and water and dried. The solvent isremoved in vacuo, leaving a solid residue which is recrystallized from abenzene-hexane mixture to give rosettes, mp 171°-173° C., of1,3-dihydro-1'-phenoxycarbenyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₅ H₂₃ NO₂ S: 74.78%C; 5.77%H; 3.49%N. Found:75.04%C; 5.84%H; 3.43%N.

EXAMPLE 4

a. A mixture of 3.0 g of1,3-dihydro-1'-phenoxycarbonyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine],Example 3, 8.0 g of potassium hydroxide pellets in 50 ml of ethyleneglycol is stirred at 155° C. until a clear solution results. Thesolution is permitted to cool, diluted with water and the biphasicmixture extracted thrice with chloroform. The combined chloroformextracts are washed carefully with water and dried and the chloroformremoved leaving a solid residue. The residue is recrystallized from anacetone-hexane to give prisms, mp 142°-144° C. of1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₁₈ H₁₉ NS: 76.83%C; 6.80%H; 4.98%N; 11.39%S.Found: 77.05%C; 6.84%H; 4.68%N; 11.26%S.

EXAMPLE 5

A mixture of 2.8 g of 1,3-dihydro-3-phenylspiro[benzo(c)thiophene],Example 4a, 1.4 g of benzyl chloride and 3.5 g of sodium bicarbonate in50 ml of dimethylformamide is stirred at 70° C. for two hours Water isadded to the cooled mixture and the biphasic mixture is extracted fourtimes with methylene chloride. The methylene chloride extracts are driedand concentrated in vacuo leaving an oily residue which crystallizes instanding. The product is recrystallized from an ether-hexane mixture togive fine needles, mp 144°-145° C. of1'-benzyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₅ H₂₅ NS: 80.82%C; 6.78%H; 3.78%N; 8.63%S.Found: 80.81%C; 6.68%H; 3.66%N; 8.76%S.

EXAMPLE 6

A mixture of 3.9 g of1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4,3.4 g of dibenzoyl peroxide, 4.0 g of potassium carbonate in 60 ml ofbenzene is stirred at a temperature of 65°-70° C. for 16 hours beforebeing filtered. The filtrate is washed and dried and the solvent removedin vacuo, leaving a crude oily product. The product is chromatographedthrough a silica gel column with a methylene chloride eluant to provide1'-benzoyloxy-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₅ H₂₃ NO₂ S: 74.78%C; 5.77%H; 3.48%N. Found:74.67%C; 5.82%H; 3.33%N.

EXAMPLE 7

A mixture of 0.6 g of1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4,0.7 g of γ-chloro-4-fluorobutyrophenone ethylene ketal, 0.5 g ofpotassium iodide and 0.5 g of sodium bicarbonate in 15 ml ofdimethylformamide is stirred at 80° C. for 16 hours. The reactionmixture is permitted to cool and then diluted with methylene chloride.The diluted mixture is filtered and the filtrate concentrated in vacuoleaving an oil which crystallizes with cooling. The solid product isrecystallized from an ether-pentane mixture to give tannish crystals, mp121°-122° C. of1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal.

Analysis: Calculated for C₃₀ H₃₂ FNO₂ S: 73.59%C; 6.59%H; 2.86%N. Found:73.81%C; 6.33%H; 2.74%N.

EXAMPLE 8

A sample of the oil,1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal, oil of Example 7, is stirred with an excess of 3N hydrochloricacid in ethanol for 16 hours. The excess acid and ethanol are removed invacuo and the residue taken up with a mixture of 20% sodium hydroxideand a methylene chloride mixture. The biphasic mixture is permitted toseparate and the organic phase is collected and dried and the solventremoved leaving a reddish oil which crystallizes with cooling. The solidproduct is recrystallized from an ether-pentane mixture to givecrystals, mp 118°-120° C., of1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₈ H₂₈ FNOS: 75.47%C; 6.33%H; 3.14%N; 7.20%S.Found: 75.74%C; 6.45%H; 2.93%N; 7.21%S.

EXAMPLE 9

A sample of3-(4-chlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine],Example 2, is treated according to the procedure of Example 3, to obtain3-(4-chlorophenyl-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine],as a glassy solid. This solid is chromatographed through a silica gelcolumn with an eluant of methylene chloride to obtain a pure white solidproduct, mp 211°-212° C.

Analysis: Calculated for C₂₅ H₂₂ ClNO₂ S: 68.81%C; 5.08%H; 3.21%N.Found: 69.04%C; 5.03%H; 2.97%N.

EXAMPLE 10

A cold stirred solution of1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4,and triethylamine in 50 ml of chloroform is treated dropwise with asolution of acetyl chloride in chloroform to provide1'-acetyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

EXAMPLE 11

A solution of1'-acetyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine],Example 10, in tetrahydrofuran is treated carefully with a stirredsuspension of lithium aluminum hydride in tetrahydrofuran to provide1'-ethyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

EXAMPLE 12

a. 13.3 ml of boron trifluoride etherate are added to a well stirredsolution of 6.0 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine,Example 1a, and 9 ml of 4-methylbenzyl mercaptan in 13.3 ml of glacialacetic acid. After this addition the reaction mixture is heated at60°-65° C. for two hours. Thereafter any excess reagents are removed invacuo at 70° C., leaving a residue which is stirred with 50 ml of 2Nhydrochloric acid and 50 ml of ether producing a semisolid product in aresultant intermediate layer. This semisolid is collected and convertedto its free base with a 20% sodium hydroxide solution. The free base isconverted to a hydrobromide which is recrystallized from amethanol-ether mixture, leaving a white solid, mp 182°-184° C., of4-(2-fluorophenyl-1-methyl-4-(4-methylbenzylthio)piperidinehydrobromide.

b. A solution of 0.7 g sodium hydride in 50% mineral oil in 20 ml ofdimethylsulfoxide is added over a five minute span to a mixture of 4.1 gof 4-(2-fluorophenyl)-1-methyl-4-(4-methylbenzylthio)piperidine, freebase of a, in 15 ml of dimethylsulfoxide. After total addition, thereaction mixture is stirred for 30 minutes before being poured into 100ml of ice-water. The biphasic mixture is filtered collecting a tan solidwhich is dissolved in dichloromethane and then column chromatographed onan alumina/ether column with an ether eluant. The chromatographedproduct is recrystallized from an ether-hexane mixture to provide theproduct, mp 121°-122° C., of1,3-dihydro-1'-methyl-3-(4-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₀ H₂₃ NS: 77.62%C; 7.49%H; 4.53%N. Found:77.63%C; 7.67%H; 4.35%N.

EXAMPLE 13

A solution of 1.0 g of1,3-dihydro-1'-methyl-3-(4-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine],Example 12 in 10 ml of dichloromethane is added to a stirring slurry of0.6 g of phenyl chloroformate and 0.2 g of sodium bicarbonate in 20 mlof dichloromethane. After addition, the mixture is permitted to stir atambient temperature for 24 hours before being successively filtered,diluted with 50 ml of methylene chloride, extracted with a 10% sodiumhydroxide solution, extracted with water, dried and filtered. Thesolvent is removed, leaving an oil. The oil is column chromatographed ona silica gel/methylene chloride column with a methylene chloride eluantto obtain a white fluffy solid which is recrystallized from abenzene-hexane mixture to obtain the product, mp 179°-180° C., of1,3-dihydro-3-(4-methylphenyl)-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₆ H₂₅ NO₂ S: 75.15%C; 6.06%H; 3.37%N. Found:75.24%C; 6.10%H; 3.16%N.

EXAMPLE 14

A mixture of 0.5 g of1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4,0.4 g of cyclopropylcarbonyl chloride and 1.0 g of sodium bicarbonate in20 ml of dichloromethane is stirred at ambient temperature for 16 hours.The well stirred mixture is filtered and the filtrate is concentrated todryness. The residue is passed through a silica gel/ether column with anether eluant to provide pure1'-cyclopropylcarbonyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₂ H₂₃ NOS: 75.60%C; 6.63%H; 4.01%N. Found:75.56%C; 6.69%H; 3.71%N.

EXAMPLE 15

A mixture of 14.4 g of3-(4-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine],Example 9, 220 ml of ethylene glycol and 35.3 g of potassium hydroxidepellets is treated according to the manipulative procedure of Example 4,above, to provide a yellow-tinted white crystalline solid. This solid isswirled with pentane and then permitted to stand at 0° C. for 16 hoursbefore the mixture is filtered to provide a white powder which isrecrystallized from an acetone-hexane mixture to provide the product, mp138°-140° C., of3-(4-chlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₁₈ H₁₈ ClNS: 68.46%C; 5.75%H; 4.44%N;11.23%Cl. Found: 68.48%C; 5.81%H; 4.34%N; 11.27%Cl.

EXAMPLE 16

1.4 g of sodium bicarbonate and 1.4 g of potassium iodide are added to amixture of 2.0 g of3-(4-chlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine],Example 15 and 2.0 g of γ-chloro-4-fluorobutyrophenone ethylene ketal in20 ml of dimethylformamide. The reaction mixture is heated with stirringat 80°-85° C. for 17 hours. The mixture is permitted to cool to ambienttemperature before being diluted with 50 ml of chloroform. The dilutedsolution is concentrated to dryness and the residue partitioned between100 ml of methylene chloride and 50 ml of water. The two layers areshaken and then permitted to separate. The organic layer is washedsequentially with water and a saturated sodium chloride solution anddried effecting an oil. The oil is column chromatographed on an aluminacolumn with ether to provide the clear oil of3-(4-chlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal.

Analysis: Calculated for C₃₀ H₃₁ ClFNO₂ S: 68.76%C; 5.96%H; 2.6%N.Found: 68.63%C; 5.89%H; 2.71%N.

EXAMPLE 17

A mixture of 2.0 g of3-(4-chlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine],Example 15, 0.7 g of chloromethylcyclopropane, 1.4 g of potassium iodideand 1.4 g of sodium bicarbonate in 20 ml of dimethylformamide is heatedwith stirring at 80°-85° C. for 17 hours. The reaction mixture ispermitted to cool to ambient temperature before being diluted with 75 mlof water and 30 ml of methylene chloride. The aqueous phase is extractedtwice with methylene chloride and all the methylene chloride solutionsare combined. The combined solutions are washed, sequentially, withwater and saturated sodium chloride solution and then dried effecting aclear oil. The oil is chromatographed on an alumina column with an ethereluant to obtain the oil with enhanced purity. This oil is converted toits maleic acid salt which is recrystallized from an acetone-ethermixture to obtain the salt, mp 217.5°-218° C. of3-(4-chlorophenyl)-1'-cyclopropylmethyl-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate.

Analysis: Calculated for C₂₂ H₂₄ ClNS.C₄ H₄ O₄ : 64.25%C; 5.81%H;2.88%N; 7.30%Cl Found: 64.13%C; 5.82%H; 2.77%N; 7.36%Cl.

EXAMPLE 18

A reaction mixture of 4.2 g of3-(4-chlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal, crude oil of Example 16, and 22 ml of 3N hydrochloric acid in 60ml of ethanol is stirred at ambient temperature for 20 hours and thencooled to 0° C. for an additional 20 hours. Any gummy precipitate isremoved by filtration and the filtrate is subjected to rotaryevaporation at 50° C. leaving an orange residue. The residue isequilibrated with 50 ml of 20% sodium hydroxide and 100 ml of a 1:1mixture of ether and methylene chloride. The layers are separated andthe aqueous layer is extracted with an additional 40 ml of the aforesaidether, methylene chloride mixture. The organic portions are combined andthese combined portions are diluted with 50 ml of ether and thensequentially washed with water and saturated sodium chloride, dried andevaporated leaving a clear orange oil. The oil is chromatographed on asilica gel column with an eluant of 5% methanol in methylene chloridemixture, providing a purified oil. The oil is dissolved in ether andconverted to its hydrobromide salt, a white powder. The powder isrecrystallized twice from a methanol-ether mixture to provide the salt,mp 240°-241° C., of3-(4-chlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]hydrobromide.

Analysis: Calculated for C₁₈ H₂₂ ClFNOS.HBr: 59.96%C; 5.03%H; 2.05%N.Found: 60.03%C; 4.85%H; 2.36%N.

EXAMPLE 19

a. A reaction mixture of 10.0 g of4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine, Example 1a, 17.5 ml of3,4-dichlorobenzyl mercaptan and 22 ml of boron trifluoride etherate in22 ml of glacial acetic acid is stirred at 60°-65° C. for 16 hours.Thereafter, the solvent is removed under reduced pressure and theresidue triturated with a mixture of ether and 1N hydrochloric acid. Themixture is stirred at 0° C. for two hours and then the resulting whitecrystalline precipitate is collected by filtration. The precipitate isrecrystallized from an acetone-ether mixture, leaving colorless needles,mp 188°-190° C., of4-(3,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidinehydrochloride.

b. 8.2 g of4-(3,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine, freebase of a, in 20 ml of dimethylsulfoxide are carefully added over a 20minute span to a cooled solution of sodium methylsulfinylmethideprepared by heating 1.2 g of sodium hydride (50%) in 50 ml ofdimethylsulfoxide at 80° C. for 30 minutes. After total addition, thereaction mixture is stirred at ambient temperature for 30 minutes andthen quenched with water. The biphasic mixture is extracted withmethylene chloride and the methylene chloride extract is dried andconcentrated, leaving a brownish oil which crystallizes with standing.The product is converted, in ether, to its maleic acid salt which isrecrystallized from an acetone-ether mixture to give the salt, mp212°-213° C., of3-(3,4-dichlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]maleate.

Analysis: Calculated for C₁₉ H₁₉ Cl₂ NS.C₄ H₄ O₄ : 57.50%C; 4.83%H;2.95%N, 14.76%C. Found: 57.75%C; 4.81%H; 2.72%N; 14.49%C.

EXAMPLE 20

a. A sample of 2-bromo-1,4-difluorobenzene is treated according to themulti-step procedure of Example 1a to ultimately obtain4-(2,5-difluorophenyl)-4-hydroxy-1-methylpiperidine, which is convertedto its maleic acid salt which is recrystallized from an acetone-ethermixture to obtain the pure salt, m.p. 163°-165° C.

b. A mixture of 4-(2,5-difluorophenyl)-4-hydroxy-1-methyl-piperidine,free base of a, 4 ml of boron trifluoride etherate, 5 ml of benzylmercaptan and 5 ml of glacial acetic acid is stirred at 65° C. for 16hours. Excess acid is removed under reduced pressure with the residueequilibrated with 0.5N hydrochloric acid and ether and the resultingsolution is stirred at 10°-20° C. for four hours. The resultingcrystalline precipitate is sequentially collected by filtration,basified and extracted with ether providing the desired product as anoil. The oil is converted to its maleic acid salt which isrecrystallized from an acetone-ether mixture to provide prisms, m.p.164°-166° C. of 4-benzylthio-4-(2,5-difluorophenyl)-1-methylpiperidinemaleate.

c. A solution of sodium methylsulfinylmethide which was prepared byheating 250 mg of sodium hydride (50% dispersion, washed with pentane)in 10 ml of dimethylsulfoxide at 80° C. for 30 minutes is added over afive-minute span at ambient temperature to a mixture of4-benzylthio-4-(2,5-difluorophenyl)-1-methylpiperidine, free base of b,in 5 ml of dimethylsulfoxide. After total addition, the mixture isstirred at ambient temperature for 30 minutes before being poured onto50 g of ice water. The mixture is extracted thrice with methylenechloride and the combined extracts are washed with water and dried. Themethylene chloride is removed under vacuum, leaving a solid residue. Theresidue is recrystallized from an ether-pentane mixture to give granularcrystals, m.p. 136°-317° C. of6-fluoro-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₁₉ H₂₀ FNS: 72.81%C; 6.42%H; 4.47%N; 6.06%F;10.23%S. Found: 72.52%C; 6.46%H; 4.27%N; 5.88%F; 10.49%S.

EXAMPLE 21

A mixture of 0.3 g of6-fluoro-1,3-dihydro-1'-methyl-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]and 0.3 g of phenyl chloroformate in 10 ml of methylene chloride whichwas previously stirred at ambient temperature for 16 hours issequentially quenched with water, washed with 10% sodium hydroxide anddried. The reaction mixture is concentrated under vacuum leaving aviscous oil which crystallized with standing. The solid product isrecrystallized from an ether-pentane mixture to give prisms, m.p.156°-158° C. of6-fluoro-1,3-dihydro-3-phenyl-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₅ H₂₂ FNO₂ S: 71.57%C; 5.29%H; 3.34%N. Found:71.65%C; 5.38%H; 3.15%N.

EXAMPLE 22

A solution of 2.5 g of3-(3,4-dichlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine],free base of Example 19, and 1.3 g of phenyl chloroformate in 30 ml ofmethylene chloride is stirred at ambient temperature for 16 hours. Thewell stirred solution is washed successively with dilute sodiumhydroxide and water and then dried, effecting a crystalling product. Theproduct is recrystallized from an acetone-pentane mixture to give fineneedles, m.p. 200°-202° C. of3-(3,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₅ H₂₁ Cl₂ NO₂ S: 63.83%C; 4.50%H; 2.98%N.Found: 63.71%C; 4.56%H; 2.93%N.

EXAMPLE 23

a. 82 ml of boron trifluoride etherate are added to a mixture of 30.0 gof 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine of Example 1a and 82ml of 2-methylbenzyl mercaptan. The resulting solution is stirred andheated at 75° C. for six hours and then the excess reagents aredistilled at 80°-100° C. The oil remaining in the flask is stirred with250 ml of 2N HCl and 500 ml of ether for one hour after which 1500 ml ofice is added to form a slurry. The slurry is stirred an additional hourand filtered to yield a white solid which is washed with ether and airdried. The material is recrystallized from methanol-acetone-ether togive the product,4-(2-fluorophenyl)-1-methyl-4-(2-methylbenzylthio)piperidinehydrochloride. An elemental analysis sample was further recrystallizedfrom acetone-ether to give a sample with constant melting point of206°-208° C.

Analysis: Calculated for C₂₀ H₂₄ FNS.HCl: 65.64%C; 6.89%H; 3.83%N.Found: 65.46%C; 6.82%H; 3.55%N.

B. A 0.73 g sample of sodium hydride, 50% in mineral oil, is cleaned bytriturating with hexane. To the cleaned sodium hydride, is added 20 mlof dimethylsulfoxide and the solution heated in an oil bath at 80°-90°C. for 30 minutes. The solution is cooled to room temperature and 4.05 gof 4-(2-fluorophenyl)-1-methyl-4-(2-methylbenzylthio)piperidine ofExample 23a in 15 ml of dimethylsulfoxide is added over a 5-minuteperiod. The reaction is stirred for thirty minutes, poured into 100 mlof ice-water, and filtered. The resulting tan solid is dissolved indichloromethane and chromatographed on an Al₂ O₃ /ether column (elutingwith ether) m.p. 132°-143° C. The sample is recrystallized fromether-hexane to obtain1,3-dihydro-1'-methyl-3-(2-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine],m.p. 132°-134° C.

Analysis: Calculated for C₂₀ H₂₃ NS: 77.62%C; 7.49%H; 4.53%N. Found:77.63%C; 7.67%H; 4.35%N.

EXAMPLE 24

A suspension of3-(3,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine](2.35 g), 7.0 g of potassium hydroxide (85%) in 30 ml of ethylene glycolis stirred at 160° C. for 30 minutes. The mixture is cooled, dilutedwith water and extracted with 3 portions (100 ml) of dichloromethane.Following drying (MgSO₄) and evaporation in vacuo, the crude amine isconverted to a crystalline maleate in ether. Recrystallization frommethanol-ether gives rhombic crystals of3-(3,4-dichlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleatem.p. 192°-193° C.

Analysis: Calculated for C₁₈ H₁₇ Cl₂ NS.C₄ H₄ O₄ : 56.65%C; 4.54%H;3.00%N; 15.20%Cl. Found: 56.75%C; 4.51%H; 2.88%N; 14.91%Cl.

EXAMPLE 25

A mixture of 1.5 g of the free base3-(3,4-dichlorophenyl)-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidine]of Example 24, 1.3 g of γ-chlorobutyrophenone ethylene ketal, 0.9 g ofpotassium iodide, 0.9 g of sodium bicarbonate in 15 ml of anhydrousdimethylformamide is stirred at 80° C. for 16 hours. The mixture isdiluted with ice-water and extracted three times with CH₂ Cl₂. The CH₂Cl₂ solution is dried (K₂ CO₃) and concentrated in vacuo to an oilyresidue. Purification is carried out by column chromatography(alumina-ether) and upon treatment with ethereal-HBr, a crystallinehydrobromide is obtained with simultaneous cleavage of the ketal ring.Recrystallization of the granular hydrobromide from methanol-ether givescolorless crystals of3-(3,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]hydrobromide.

Analysis: Calculated for C₂₈ H₂₆ Cl₂ FNOS.HBr: 56.47%C; 4.57%H; 2.23%N.Found: 56.43%C; 4.59%H; 2.31%N.

EXAMPLE 26

A mixture of the free base3-(3,4-dichlorophenyl)-1,3-dihydrospiro[benzo[c]thiophene-1,4'-piperidine]of Example 24 (2.0 g), 1.8 g of γ-chloro-4-fluorobutyrophenone ethyleneketal, 0.9 g of sodium bicarbonate, 0.9 g of potassium iodide in 15 mlof anhydrous DMF is stirred at 80° C. for 16 hours. The cooled mixtureis diluted with water and ether and the layers are separated. Theorganic solution is washed with water, dried (MgSO₄) and concentrated toan oily residue in vacuo. Purification of the crude product isaccomplished by passing through a short alumina-ether column. Elutionwith ether gives a pale yellowish oil which is converted to acrystalline maleate in ether. Recrystallization from acetone-ether givesgranulars, m.p. 116°-119° C. of 3-(3,4dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethylene ketal maleate.

Analysis: Calculated for C₃₀ H₃₀ Cl₂ FNO₂ S.C₄ H₄ O₄ : 60.52%C; 5.08%H;2.08%N. Found: 60.53%C; 5.05%H; 1.86%N.

EXAMPLE 27

a. A mixture of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine ofExample 1a (10.5 g), 10 g of p-fluorobenzyl mercaptan, 18 ml of borontrifluoride etherate and 10 ml of glacial acetic acid is stirred at60°-65° C. for 16 hours. The excess reagents are removed under reducedpressure at 100° and the oily residue is triturated with an excess of0.5N hydrochloric acid and 200 ml of ether. A white precipitate isfiltered after 2 hours at 5°-10° C. and is basified to give the desiredproduct. The oily amine is converted to a crystalline maleate in ether,recrystallization from methanol-ether gives colorless prisms, m.p.123°-125° C. of4-(4-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine maleate.

Analysis: Calculated for C₁₉ H₂₁ F₂ NS.C₄ H₄ O₄ : 61.45%C; 5.61%H;3.12%N. Found: 61.71%C; 5.75%H; 3.15%N.

b. A solution of sodium methylsulfinyl methide is prepared by heating0.87 g of sodium hydride in 80 ml of dimethylsulfoxide at 80° C. for 30minutes. The solution is then treated with 8.9 g of the free base4-(4-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine of Example27a in 20 ml of DMSO over 2 minutes and stirring continued for 15minutes at 80° C. before quenching with ice-water. The mixture isextracted 3 times with CH₂ Cl₂, the combined CH₂ Cl₂ solution washedwith water and dried, and concentrated to an oily residue. Purificationof the crude product is carried out by column chromatography(alumina-ether) and concentration of the combined effluent affords aheavy oil which crystallizes on cooling. Recrystallization fromether-pentane gives long needles, m.p. 109°-110° C., of3-(4-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₁₉ H₂₀ FNS: 72.81%C; 6.43%H; 4.47%N; 6.38%F.Found: 73.05%C; 6.31%H; 4.58%N; 6.23%F.

EXAMPLE 28

A mixture of3-(4-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 27 (3.6 g), 2.1 g of phenyl chloroformate in 100 ml of CH₂Cl₂ is stirred at room temperature for 64 hours. The solution is washedwith 10% aqueous NaOH, water, and dried over MgSO₄. Evaporation underreduced pressure affords a crystalline residue, m.p. 198°-200° C.Recrystallization of the crude product from acetone-pentane givesgranular crystals, m.p. 200°-201° C. of3-(4-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₅ H₂₂ FNO₂ S: 71.57%C; 5.28%H; 3.34%N. Found:71.73%C; 5.25%H; 3.20%N.

EXAMPLE 29

A mixture of3-(4-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 28 (4.3 g), 1.4 g of potassium hydroxide in 50 ml of ethyleneglycol is stirred at 160° C. for 30 minutes. The cooled mixture isdiluted with water and extracted three times with 150 ml portions ofether. The combined ether extract is washed with water (3-4 times),dried, and concentrated to an oily residue of secondary amine. Thesecondary amine is converted to its hydrochloride in a conventionalmanner by stirring without heating with hydrochloric acid for severalhours. Recrystallization from methanol-acetone-ether gives crystals,m.p. 259°-260° C. of3-(4-fluorophenyl-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]hydrochloride.

Analysis: Calculated for C₁₈ H₁₈ FNS.HCl: 64.36%C; 5.70%H; 4.17%N;5.65%F. Found: 64.09%C; 5.55%H; 4.28%N; 5.78%F.

EXAMPLE 30

A mixture of3-(4-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine](2.2 g of the free base of Example 29) 2.2 g ofγ-chloro-4-fluorobutyrophenone ethylene ketal, 1.5 g of sodiumbicarbonate, 1.5 g of potassium iodide in 25 ml of DMF is stirred at 80°C. for 16 hours. The cooled mixture is quenched with water, extracted 3times with ether and dried. Removal of the solvent in vacuo at 80° C.leaves a reddish oil which is purified by passing through a short columnof alumina packed in ether. Elution with ether gives a pure tertiaryamine which is converted into a crystalline maleate. Recrystallizationfrom acetone-ether affords colorless prisms, m.p. 175°-177° C. of1'-[3-(4-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal maleate.

Analysis: Calculated for C₃₀ H₃₁ F₂ NO₂ S.C₄ H₄ O₄ : 65.46%C; 5.64%H;2.24%N. Found: 65.28%C; 5.71%H; 2.21%N.

EXAMPLE 31

A solution of1'-[3-(p-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydro-spiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 30 (2.3 g of the free base) in 200 ml of ether and 10ml of methanol is saturated with anhydrous hydrogen bromide. Afterstanding at room temperature for 2 hours, the mixture is carefullyneutralized with 1N ammonia and the ether solution is washed 3 timeswith water, dried and concentrated to an oily residue. The free base isconverted to a crystalline maleate in ether and recrystallization fromacetone-ether gives off-white prisms, m.p. 149°-150° C., of1'-[3-(4-fluorobenzoyl)propyl]-3-(4-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate.

Analysis: Calculated for C₂₈ H₂₇ F₂ NOS.C₄ H₄ O₄ : 66.31%C; 5.40%H;2.42%N; 6.55%F. Found: 66.41%C; 5.22%H; 2.36%N; 6.64%F.

EXAMPLE 32

a. 59.7 g of 2-chlorobenzylmercaptan, followed by 55 ml of borontrifluoride etherate are added to 25 g of4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine of Example 1a in 55 mlof acetic acid. The reaction is stirred at 55°-65° C. for 20 hours. Theexcess acid is removed under reduced pressure at 80°-100° C. The oilyresidue is then equilibrated with 200 ml of 2N hydrochloric acid and 200ml of ether. The ether, and two more 125 ml portions of ether, isdecanted off. The oil and water mixture is diluted to 650 ml volume withwater and is stored at 0° C. for about three days to produce crystals.The mixture is diluted and filtered. The precipitate is washed withwater and ether, and dried. The solid is recrystallized (acetone:ether)to a broad melting (122°-129° C.) solid. A portion of the solid isplaced in water, basified with 10% aqueous NaOH, extracted into ether,washed, dried and treated with ethereal hydrogen chloride to give awhite powder. The powder is recrystallized from acetone-ether to give awhite crystalline solid, m.p. 173°-175° C. of4-(2-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidinehydrochloride.

Analysis: Calculated for C₁₉ H₂₁ ClFNS: 59.08%C; 5.74%H; 3.63%N; 4.92%F.Found: 58.81%C; 5.63%H; 3.37%N; 5.03%F.

b. A 0.2 g portion of sodium hydride (prepared by washing a 50% oildispersion) is heated at 80° C. with stirring in 15 ml of drydimethylsulfoxide for 30 minutes. Then 2.1 g of the free base4-(2-chlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine of Example32a in 10 ml of dry DMSO is added in one portion and the oil bath isremoved. The reaction is allowed to stir without heating for 40 minutes,then is poured onto 250 cc of ice with 250 ml of ether. The layers areshaken and separated and the aqueous portion extracted again with 150 mlof ether. The combined ether is washed with two 100 ml portions of waterand one 10 ml portion of saturated sodium chloride solution, and isdried over magnesium sulfate to give an oil. The oil is chromatographedon a column of alumina with ether to a material (free base) showing onespot (Rf 0.54; 25% MeOH:CH₂ Cl₂, silica) by tlc. The product in ether istreated with excess ethereal maleic acid, washed with ether, and driedto give a white powder, m.p. 173°-176° C., of3-(2-chlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]maleate.

A small portion of the salt is recrystallized twice from acetone to givecrystals melting at 178°-178.5° C.

Analysis: Calculated for C₁₉ H₂₀ ClNS.C₄ H₄ O₄ : 61.95%C; 5.43%H;3.14%N; 7.95%Cl. Found: 62.03%C; 5.46%H; 3.10%N; 7.94%Cl.

EXAMPLE 33

a. A mixture of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine ofExample 1a (15.8 g), 12 ml of 2-fluorobenzyl mercaptan and 20 ml ofboron trifluoride etherate in 15 ml of glacial acetic acid is stirred at65°-70° C. for 16 hours. The excess reagents are removed under reducedpressure, the residue is triturated with 300 ml of 0.5N HCl and 100 mlof ether. After standing at 5°-10° C. for 30 minutes, a crystallineprecipitate is filtered, air dried and made basic with 10% aqueous NH₄OH. The liberated amine is taken up in ether, dried and concentrated toa yellowish oil which is then converted to its maleate in ether,recrystallization of the crude salt from methanol-ether gives colorlessprisms, m.p. 153°-154° C. of4-(2-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine maleate.

Analysis: Calculated for C₁₉ H₂₁ F₂ NS.C₄ H₄ O₄ : 61.45%C; 5.61%H;3.12%N. Found: 61.28%C; 5.57%H; 2.98%N.

b. A solution of sodium methylsulfinyl methide is prepared by heating1.2 g of sodium hydride in 100 ml of DMSO at 80° C. for 30 minutes. Themixture is cooled to room temperature and to it is added 12 g of thefree base 4-(2-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidinein 40 ml of DMSO over a period of 5 minutes. Following the addition, themixture is stirred at 70°-80° C. for an additional 30 minutes. Themixture is diluted with ice-water, extracted 3 times with ether. Thecombined ether solution is washed 4 times with water, dried andconcentrated to a thick oil. Chromatography over Al₂ O₃ -ether removes asmall amount of impurities and the purified amine is converted to acrystalline hydrobromide in ether. Recrystallization from methanol-ethergives colorless crystals, m.p. 263°-265° (dec.) of3-(2-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]hydrobromide.

Analysis: Calculated for C₁₉ H₂₀ FNS.HBr: 57.86%C; 5.37%H; 3.55%N;4.82%F. Found: 57.67%C; 5.47%H; 3.58%N; 4.80%F.

EXAMPLE 34

A mixture of the free amine3-(2-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 33 (6.3 g), 3.9 g of phenyl chloroformate in 100 ml ofanhydrous CH₂ Cl₂ is stirred at room temperature for 4 hours. Thereaction mixture is washed with 10% aqueous sodium hydroxide and driedover MgSO₄ for 2 hours.

Removal of solvent under reduced pressure leads to a thick oil which ispurified through a short silica gel column packed in CH₂ Cl₂. Elutionwith a large excess of CH₂ Cl₂ gave, after concentration, a colorlessoil which solidified on standing, to yield3-(2-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]m.p. 122°-123° C.

Analysis: Calculated for C₂₅ H₂₂ FNO₂ S: 71.57%C; 5.28%H; 3.34%N. Found:71.49%C; 5.23%H; 3.27%N.

EXAMPLE 35

A mixture of3-(2-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 34 (5.6 g), 18 g of potassium hydroxide in 100 ml of ethyleneglycol is stirred at 170° C. for 30 minutes. The mixture is poured intowater and extracted 3 times with ether. The ether solution is washedwith water, dried and concentrated in vacuo to give a viscous oil offree amine. A crystalline maleate is prepared and recrystallized frommethanol-acetone-ether to give a white powder of3-(2-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate.

Analysis: Calculated for C₁₈ H₁₈ FNS.C₄ H₄ O₄ : 63.59% C; 5.34%H;3.37%N; 4.57%F. Found: 63.55%C; 5.33%H; 3.10%N; 4.52%F.

EXAMPLE 36

A mixture of3-(2-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]of Example 35 (2.2 g), 2.2 g of γ-chloro-4-fluorobutyrophenone ethyleneketal compound, 1.5 g of potassium iodide, 1.5 g of sodium bicarbonatein 25 ml of DMF is stirred at 70°-75° C. for 16 hours. The cooledmixture is diluted with water and the mixture extracted 3 times withether. The ether solution, after washing with water and drying, isconcentrated in vacuo to an oily residue which is purified through ashort column of alumina, elution with ether gives a colorless oil whichis converted to a crystalline maleate, m.p. 105°-151° C. of1'-[3-(4-fluorobenzoyl)propyl]-3-(2-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal maleate.

Analysis: Calculated for C₃₀ H₃₁ F₂ NO₂ S.C₄ H₄ O₄ : 65.46%C; 5.64%H;2.24%N. Found: 65.46%C; 5.37%H; 2.12%N.

EXAMPLE 37

A solution of1'-[3-(4-fluorobenzoyl)propyl]-3-(2-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 36 (2.0 g) in 20 ml of ethanol and 20 ml of 3Nhydrochloric acid is heated on a steam bath for 30 minutes. The cooledsolution is basified with 40% aqueous sodium hydroxide and extracted 3times with ether. The combined ether solution is washed thoroughly withwater, dried and treated with an excess of ethereal maleic acid. Acrystalline maleate is recrystallized from acetone-ether to giveall-white prisms, m.p. 137°-138.5° C., of1'-[3-(4-fluorobenzoyl)propyl]-3-(2-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate.

Analysis: Calculated for C₂₈ H₂₇ F₂ NO.C₄ H₄ O₄ : 66.31%C; 5.40%H;2.42%N; 6.55%F. Found: 66.18%C; 5.34%N; 2.42%N; 6.49%F.

EXAMPLE 38

A 4.5 g sample of phenyl chloroformate in 150 ml of dichloromethane isstirred at 25° C. while 7.5 g of1,3-dihydro-1'-methyl-3-(2-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]of Example 23 in 75 ml of dichloromethane is rapidly added. The reactionis stirred a total of 24 hours at 25° C. and quenched with 225 ml of 10%aqueous NaOH solution. The organic layer is separated, washed withwater, dried over MgSO₄, filtered and evaporated to an oil. The oil iscolumn chromatographed on a silica gel/CH₂ Cl₂ column with CH₂ Cl₂ beingused for elution. The isolated product is a pale yellow oil of1,3-dihydro-3-(2-methylphenyl)-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₆ H₂₅ NO₂ S: 75.15%C; 6.06%H. Found: 74.90%C;6.05%H.

EXAMPLE 39

A solution of 16 g of potassium hydroxide dissolved in 100 ml ofethylene glycol is added to 6.0 g of1,3-dihydro-3-(2-methylphenyl)-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 38. The resulting solution is stirred and heated at 160° C.for one hour. The solution is poured into 300 ml of ice water andextracted with ether. The ether fractions are combined, washed withwater, dried over MgSO₄, filtered, and evaporated to a residue which isconverted to a white, granular, maleate salt,1,3-dihydro-3-(2-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]maleate,which is recrystallized from methanol-ether and has a m.p. 178°-179° C.

Analysis: Calculated for C₁₉ H₂₁ NS.C₄ H₄ O₄ : 67.13%C; 6.12%H; 3.40%N.Found: 67.10%C; 5.96%H; 3.14%N.

EXAMPLE 40

A mixture of 6.0 g of1,3-dihydro-3-(4-methylphenyl)-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 13, 16.0 g of potassium hydroxide and 100 ml of ethyleneglycol is stirred and heated at 160° C. for one hour. The reactionmixture is quenched with ice water and extracted with ether. The etherextracts are combined, washed with water, dried over MgSO₄, andevaporated to an oil. The oil is converted to1,3-dihydro-3-(4-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]maleate.m.p. 214°-215° C.

Analysis: Calculated for C₁₉ H₂₁ NS.C₄ H₄ O₄ : 67.13%C; 6.12%H; 3.40%N.Found: 67.05%C; 6.20%H; 3.21%N.

EXAMPLE 41

a. To 25 g of 4-(2-fluorophenyl)-4-hydroxyl-1-methylpiperidine ofExample 1a is added 50 g of m-methylbenzyl mercaptan. To this mixture isadded 68 ml of boron trifluoride etherate. The reaction is stirred at65°-70° C. for about three days. Excess reagent is then removed underaspirator pressure at 60°-100° C. The mixture is poured into 360 ml of0.5N hydrochloric acid with 300 ml of ether. An oil falls out, fromwhich the water and ether are decanted. The oil is placed under 250 mlof 0.5N hydrochloric acid and 200 ml of ether. The oil is againseparated from the solutions and is placed under 150 ml of water with 20ml of 10% aqueous sodium hydroxide solution. The suspension is dilutedfurther with 200 ml of water and is extracted with two 200 ml portionsand one 100 ml portion of ether. The combined amine ether extracts areadded to a solution of 12.5 ml of 48% aqueous hydrogen bromide in 300 mlof water to give a white salt. The mixture is allowed to stand 16 hours,then the ether is decanted off. The aqueous mixture is washed again byadding and decanting 200 ml of ether. The salt is then filtered off,washed with water and ether, and dried to a white powder, m.p. 143°-145°C., of 4-(2-fluorophenyl)-4-(3-methylbenzylthio)-1-methylpiperidinehydrobromide. A thrice recrystallized (acetone-ether) sample melts at145°-146° C.

Analysis: Calculated for C₂₀ H₂₄ FNS.HBr: 58.54%C; 6.14%H; 3.41%N.Found: 58.45%C; 6.16%H; 3.16%N.

b. A 3.43 g portion of 50% sodium hydride dispersion is washed withhexane under dry nitrogen and then heated with 100 ml of sieve drieddimethylsulfoxide at 80°-85° C. for 40 minutes. Then 18.48 g of the freebase of 4-(2-fluorophenyl)-4-(3-methylbenzylthio)-1-methylpiperidine ofExample 41a in 70 ml of dry DMSO is added over 60 seconds. The redmixture is stirred, cooled to room temperature over one hour, and pouredinto 500 cc of ice water. The aqueous mixture is extracted with three200 ml portions of dichloromethane. Combined dichloromethane extractsare washed with four 200 ml portions of water and one 100 ml portion ofsaturated aqueous sodium chloride solution; and dried over magnesiumsulfate to yield an oil. The oil is dissolved in ether, filtered,evaporated, and chromatographed on 400 ml of alumina with ether to givean oil which is dissolved in ether and treated with ethereal hydrogenbromide to give a salt. The salt is washed with ether and recrystallizedfrom methanol-acetone-ether to give a white, crystalline powder, m.p.258°-260° C. of1,3-dihydro-1'-methyl-3-(3-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]hydrobromide.

Analysis: Calculated for C₂₀ H₂₃ NS.HBr: 61.54%C; 6.20%H; 3.59%N. Found:61.27%C; 6.24%H; 3.45%N.

EXAMPLE 42

A solution of 0.70 g of the amine1,3-dihydro-3-(2-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]of Example 39, 0.76 g of γ-chloro-p-fluorobutyrophenone ethylene ketal,0.38 g of sodium bicarbonate, 0.38 g of KI, and 10 ml of anhydrous DMFis stirred and heated at 70°-80° C. for 24 hours. The reaction is workedup by pouring it into water and extracting with ether. The etherfractions are combined, washed with water, and dried over MgSO₄. Thesolution is filtered, evaporated and the resulting oil columnchromatographed on a Al₂ O₃ /ether column (eluted with ether). Theisolated product is converted to a maleate salt of1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(2-methylphenylspiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal maleate, m.p. 157°-159° C.

Analysis: Calculated for C₃₁ H₃₄ FNO₂ S.C₄ H₄ O₄ : 67.83%C; 6.18%H;2.26%N. Found: 67.78%C; 6.02%H. 2.24%N.

EXAMPLE 43

To 3.83 g of phenyl chloroformate in 850 ml of dichloromethane is addeda solution of 6.73 g of the free base3-(2-chlorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 32 in 75 ml of dichloromethane over two minutes. The reactionis stirred at ambient temperature for 64 hours, then diluted with 200 mlof dichloromethane and washed with two 300 ml portions of 5% aqueoussodium hydroxide solution, two 200 ml portions of water and one 75 mlportion of brine. The solution is dried over magnesium sulfate andevaporated in an oil. The oil is chromatographed on a silica gel withdichloromethane to given an oil of3-(-2-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].

Analysis: Calculated for C₂₅ H₂₂ ClNO₂ S: 68.88%C; 5.09%H; 3.21%N.Found: 69.36%C; 4.94%H; 3.33%N.

EXAMPLE 44

To 1.81 g of phenyl chloroformate in 40 ml of dichloromethane is added asolution of 2.98 g of the free base1,3-dihydro-1'-methyl-3-(3-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]of Example 41 in 35 ml of dichloromethane over 5 minutes. The reactionis stirred at ambient temperature for 21 hours The reaction is thendiluted with 100 ml of dichloromethane; washed with two 150 ml portionsof 5% aqueous sodium hydroxide solution, two 100 ml portions of waterand one 50 ml portion of brine; and dried over magnesium sulfate to anoil. The oil is chromatographed on silica gel with dichloromethane toyield1,3-dihydro-3-(3-methylphenyl)-1'-phenoxycarbonylspiro[benzo(c)-thiophene-1,4'-piperidine],m.p. 154°-157° C. A portion is recrystallized from toluene-hexane, m.p.157°-160° C.

Analysis: Calculated for C₂₆ H₂₅ NO₂ S: 75.16%C: 6.07%H; 3.37%N. Found:75.28%C; 6.12%H; 3.17%N.

EXAMPLE 45

To 6.19 g of3-(-2-chlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 43 in 95 ml of ethylene glycol at 150° C. is added 15.1 g of85% potassium hydroxide pellets. The reaction is stirred in a 160°-165°C. bath for 40 minutes, then cooled to room temperature and poured into250 ml of water. The mixture is diluted to 500 ml with water andextracted with three 150 ml portions of water and one 40 ml portion ofsaturated sodium chloride solution and dried over magnesium sulfate toan oil. The oil is dissolved in ether, filtered, and treated withethereal maleic acid. The crude salt is washed with ether andrecrystallized from methanol-acetone-ether to give a white salt of3-(2-chloroethyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate,m.p. 172°-173° C.

Analysis: Calculated for C₁₈ H₁₈ ClNS: 61.18%C; 5.14%H; 3.24%N; 8.21%Cl.Found: 61.47%C; 5.22%H; 3.18%N; 7.85%Cl.

EXAMPLE 46

To 2.48 g of the free base,3-(2-chlorophenyl)-1,3-dihydro-spiro[benzo[c]thiophene-1,4'-piperidine]of Example 45, in 28 ml of sieve-dried dimethylformamide with 2.78 g ofγ-chloro-p-fluorophenylbutyrophenone ethylene ketal is added 2.02 g ofsodium bicarbonate and 2.02 g of potassium iodide. The reaction is thenheated in an 85°-50° C. bath for 17 hours. The mixture is diluted with90 ml of chloroform and filtered through paper. The solution isevaporated and the oil partitioned between 140 ml of dichloromethane and75 ml of water. The dichloromethane is washed with 75 ml of water andone 25 ml portion of saturated sodium chloride solution and dried overmagnesium sulfate. The oil is chromatographed on alumina with ether andtreated with ethereal oxalic acid to give a salt. The salt is washedwith ether and recrystallized from methanol-acetone-ether (m.p.200°-201° C.) to give a white solid of3-(2-chlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal oxalate, m.p. 200°-201° C.

Analysis: Calculated for C₃₀ H₃₁ ClFNO₂ S.C₂ H₂ O₄ : 62.59%C; 5.42%H;2.28%N. Found: 62.53%C; 5.44%H; 2.26%N.

EXAMPLE 47

a. To 14.45 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine ofExample 1a is added 39.45 g of 2,4-dichlorobenzyl mercaptan followed by40 ml of boron trifluoride etherate. The reaction is stirred at 80°-85°C. for about 4 days. The excess reagent is removed under aspiratorpressure to 110° C. and the residual oil poured into 200 ml of 0.5Nhydrochloric acid and 200 ml of ether. The mixture is allowed to stand18 hours, the ether decanted off and two more 200 ml portions of etherare added and decanted. The crude precipitate is filtered, washed with75 ml of water and three 125 ml portions of ether, and dried to anapparently mixed salt. A portion of the salt is basified in aqueousammonium hydroxide, extracted with ether, washed with water and brine,and dried over magnesium sulfate. The ethereal solution is treated withethereal hydrogen bromide to give a salt. The salt is washed with etherand dried to give a white powder of4-(2,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidinehydrobromide, m.p. 208.5°-210° C.

Analysis: Calculated for C₁₉ H₂₀ Cl₂ FNS.HBr: 49.05%C; 4.55%H; 3.01%N.Found: 48.87%C; 4.52%H; 2.96%N.

b. A 0.3 g of sodium hydride (50%) is washed with hexane nitrogen andheated at 80° C. with 11 ml of dry dimethylsulfoxide for 30 minutes.Then 1.68 g of the free base,4-(2,4-dichlorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine ofExample 47a in 7.3 ml of dry DMSO is added at once and the heatingremoved. The reaction is stirred under nitrogen, while cooling to roomtemperature over 45 minutes, then poured onto ice and extracted with 50ml of ether and 1 50 ml of dichloromethane. Combined organic phases arewashed with two 100 ml portions of water and one 25 ml portion of brine,and dried over magnesium sulfate to an oil. The oil is chromatographedon alumina with ether to give an oil. The oil, in ether, is treated withethereal hydrogen bromide to form a salt. The salt is washed with etherand recrystallized from acetone-ether to give a yellowish-white salt of3-(2,4-dichlorophenyl)-1,3-dihydro-1'-methyl-spiro(benzo(c)thiophene-1,4'-piperidine)hydrobromide, m.p. 259.5°-261° C. A portion of the crudesalt is recrystallized thrice from methanol-acetone ether to give a m.p.260°-261° C.

Analysis: Calculated for C₁₉ H₁₉ Cl₂ NS.HBr: 51.26%C; 4.53%H; 3.15%N;15.93%Cl. Found: 51.43%C; 4.56%H; 3.15%N; 15.65%Cl.

EXAMPLE 48

To 1.34 g of1,3-dihydro-3-(3-methylphenyl)-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 44 in 22 ml of ethylene glycol, under nitrogen, at 150° C. isadded 3.44 g of 85% aqueous potassium hydroxide. The reaction is stirredat 160° C. for 40 minutes, then is poured into 50 ml of ice water,diluted to 120 ml and extracted with two 50 ml portions ofdichloromethane. The combined dichloromethane extract is washed with two50 ml portions of water and one 20 ml portion of saturated sodiumchloride solution, and dried over magnesium sulfate to an oil. The oilis purified by swirling and decanting one 50 ml portion and two 25 mlportions of boiling hexane. The evaporated hexane gives an oil (freebase) which is dissolved in ether, treated with ethereal maleic acid,and recrystallized from acetone to a white powder of1,3-dihydro-3-(3-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]maleate,m.p. 175° -176° C.

Analysis: Calculated for C₁₉ H₂₁ SN.C₄ H₄ O₄ : 67.14%C; 6.12%H; 3.41%N.Found: 67.29%C; 6.13%H; 3.30%N.

EXAMPLE 49

To 4.02 g of the free base3-(2-chlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 46 in 250 ml of ether with 15 ml of methanol is added120 ml of an ethereal hydrogen bromide solution. The reaction is allowedto stir for two hours, then 120 ml of 1:4, 58% ammonium hydroxide:wateris added with stirring to dissolve all material. The layers areseparated and the ether washed with three 100 ml portions of water andone 25 ml portion of saturated aqueous sodium chloride solution anddried over magnesium sulfate to yield a solid. The solid is stirred in amixture of 125 ml of ether and 64 ml of 15:1, water:58% ammoniumhydroxide for one hour. The layers are separated and the aqueous layerwashed with two 50 ml portions of ether, and then filtered and dried toa solid. The combined ether solutions are washed with water and brine,dried, evaporated, and the solids recrystallized from ethyl acetate andcombined to give a solid of3-(2-chlorophenyl)-1'-[3-(4-fluorobenzoylpropyl]dihydrospiro[benzo(c)thiophene-1,4'-piperidine],melting at 144°-148° C.

Analysis: Calculated for C₂₈ H₂₇ ClFNOS: 70.07%C; 5.67%H; 2.92%N;7.39%Cl. Found: 69.81%C; 5.54%H; 2.79%N; 7.29%Cl.

EXAMPLE 50

To 5.25 g of the free base,1,3-dihydro-3-(3-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]of Example 48, in 65 ml of sieve-dried dimethylformamide is added 5.43 gof γ-chloro-p-fluorobutyrophenone ethylene ketal, followed by 3.6 g ofsodium bicarbonate and 3.6 g of potassium iodide. The reaction isstirred in an 85° C. bath for 24 hours, then diluted with 130 ml ofchloroform and filtered. The solvent is removed and the residual oil ispartitioned between 250 ml of dichloromethane and 150 ml portion ofwater and one 35 ml portion of saturated sodium chloride solution anddried over magnesium sulfate to an oil. The oil is chromatographed onalumina with ether and is converted to the maleate salt by treatmentwith ethereal maleic acid. Recrystallization from acetone-ether yields1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(3-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal maleate, m.p. 155°-157° C.

Analysis: Calculated for C₃₁ H₃₄ FNO₂ S.C₄ H₄ O₄ : 67.84%C; 6.18%H;2.26%N. Found: 67.76%C; 6.19%H; 2.15%N.

EXAMPLE 51

To 8.5 g of phenyl chloroformate in 130 ml of dry dichloromethane undernitrogen is added a solution of 15.56 g of the free base of3-(2,4-dichlorobenzylthio)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 47 in 100 ml of dry dichloromethane over 15 minutes. Thereaction is stirred at ambient temperature for 21 hours, then dilutedwith 450 ml of dichloromethane, washed with two 300 ml portions of 10%aqueous sodium hydroxide solution, two 300 ml portions of water and one100 ml portion of brine and dried over magnesium sulfate to an oil. Theoil is chromatographed on silica gel with dichloromethane to give aclear oil of3-(2,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine].

Elemental Analysis: Calculated for C₂₅ H₂₁ Cl₂ NO₂ S: 63.84%C; 4.50%H;2.98%N. Found: 63.71%C; 4.52%H; 2.79%N.

EXAMPLE 52

A solution of 2.85 g of the free base1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(2-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 42, 30 ml of absolute ethanol, and 30 ml of 3N HClsolution is refluxed for 45 minutes. The reaction is cooled, made basicwith 40% aqueous NaOH solution, and extracted with CH₂ Cl₂. The CH₂ Cl₂fractions are combined, washed with water, and dried over MgSO₄. Thesolution is filtered and evaporated to a solid which is recrystallizedfrom ethyl acetate to give a pure product of1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(2-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine],m.p. 143°-145° C.

Analysis: Calculated for C₂₉ H₃₀ FNOS: 75.78%C; 6.58%H; 3.05%N. Found:75.51%C; 6.70%N; 2.85%N.

EXAMPLE 53

To 15.12 g of3-(2,4-dichlorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 51 in 216 ml of ethylene glycol at 150° C., under nitrogen,is added 34.2 g of 85% potassium hydroxide pellets. The reaction isstirred at 160° C. for 45 minutes, then poured into 1.4 l of water andextracted with three 350 ml portions of dichloromethane. The combineddichloromethane extract is washed with two 400 ml portions of water andone 100 ml portion of saturated aqueous sodium chloride solution anddried over magnesium sulfate to an oil. The oil is purified by decantingwith three 225 ml portions of boiling hexane to yield a solid. A portionof the solid is dissolved in ether and treated with ethereal maleic acidto give a salt. The salt is washed with ether and recrystallized frommethanol-acetone-ether to a white powder of3-(2,4-dichlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate,m.p. 171°-172.5° C.

Analysis: Calculated for C₁₈ H₁₇ Cl₂ NS.C₄ H₄ O₄ : 56.66%C; 4.54%H;3.00%N; 15.20%Cl. Found: 56.49%C: 4.54%H; 2.81%N; 14.99%Cl.

EXAMPLE 54

To 3.0 g of the free base3-(2,4-dichlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]of Example 53 in 35 ml of sieve-dried dimethylformamide is added 2.62 gof γ-chloro-p-fluorobutyrophenone ethylene ketal, followed by 1.7 g ofsodium bicarbonate and 1.7 g of potassium iodide. The reaction isstirred at 80°-90° C. for 20 hours. The mixture is diluted with 75 ml ofchloroform, filtered, and rotary evaporated at 75° C. to an oil. The oilis partitioned between 125 ml of dichloromethane and 85 ml of water. Themixture is diluted with 10 ml of saturated aqueous sodium bicarbonatesolution, and the organic layer separated and washed with one 80 mlportion of water and one 30 ml portion of saturated sodium chloridesolution. The dichloromethane solution is dried and evaporated to anoil. The oil is chromatographed on alumina with ether and a portion ofthe resultant oil is placed in ether and treated with ethereal oxalicacid to give a salt. The salt is washed with ether and recrystallizedfrom methanol-acetone-ether to yield a white powder of3-(2,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal oxalate, m.p. 164°-165° C.

Analysis: Calculated for C₃₀ H₃₀ Cl₂ FNO₂ S.C₂ H₂ O₄ : 59.26%C; 4.97%H;2.16%N. Found: 59.15%C; 4.81%H; 2.11%N.

EXAMPLE 55

a. To 26.33 g of 4-(2-fluorophenyl)-4-hydroxy-1-methylpiperidine ofExample 1a with 20 ml (approximately 23.3 g) of m-fluorobenzylmercaptanin 25 ml of glacial acetic acid is added 33 ml of boron trifluorideetherate. The reaction is stirred at 65°-68° C. for 44 hours, then anadditional 17 ml of boron trifluoride etherate is added and stirring at65°-68° C. is resumed for about three more days. Excess solvent isremoved under reduced pressure to 110° C. The residue is mixed with 450ml of 0.5N HCl and 175 ml of ether to form an oil. The oil and waterlayer is washed by decanting with ether, then the aqueous acid iscarefully decanted from the oil. The oil is placed under water, treatedto pH=9-10 with ammonium hydroxide and extracted with ether. Theethereal solution is washed with water until neutral, then is pouredinto a solution of 30 ml of 48% hydrogen bromide diluted to 350 ml toform a salt. The salt is filtered off, washed with a small amount ofwater and a generous amount of ether to give a white salt of4-(3-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidinehydrobromide, m.p. 176°-178.5° C. A thrice recrystallized(methanol-acetone-ether) sample melts at 178°-179.5° C.

Analysis: Calculated for C₁₉ H₂₁ F₂ NS.HBr: 55.08%C; 5.35%H; 3.38%N.Found: 55.05%C; 5.38%H; 3.38%N.

b. To 1.404 g of sodium hydride (from 2.37 g of a 50% dispersion), undernitrogen, is added 120 ml of sieve-dried dimethylsulfoxide. The mixtureis stirred in an 80°-85° C. bath for 35 minutes, then cooled to roomtemperature. A solution of 14.0 g of the free base4-(3-fluorobenzylthio)-4-(2-fluorophenyl)-1-methylpiperidine of Example55a in 47 ml of DMSO is added over 60 seconds and the solution stirredfor one hour. The reaction is then poured into 700 ml of ice water andextracted with three 200 ml portions of dichloromethane. The combineddichloromethane extracts are washed with three 300 ml portions of waterand one 75 ml portion of saturated sodium chloride solution, and driedover magnesium sulfate to an oil. The oil is chromatographed on aluminawith ether to give crystals. A portion of this, in ether is treated withethereal maleic acid. The resulting salt is washed with ether and driedto give a powder of3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]maleate,m.p. 137°-140° C. A twice recrystallized portion melts at 138.5°-140.5°C. Upon continued heating, a new crystalline form develops whichcollapses in the 175°-180° C. range.

Analysis: Calculated for C₁₉ H₂₀ FNS.C₄ H₄ O₄ : 64.32%C; 5.63%H; 3.26%N;4.42%F. Found: 64.26%C; 5.58%H; 2.95%N; 4.58%F.

EXAMPLE 56

To 3.26 g of the free base3-(2,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 54 in 30 ml of warm ethanol is slowly added 30 ml of 3Nhydrochloric acid. The mixture is heated over a steam bath for 45minutes. 10 ml of additional ethanol is added and heating is resumed for45 minutes. The reaction is then cooled to room temperature and basifiedwith 40% aqueous sodium hydroxide solution. The mixture is diluted with200 ml of water and extracted with three 80 ml portions ofdichlorothane. The combined dichloromethane extracts are washed with two100 ml portions of water, one 50 ml portion of saturated aqueous sodiumchloride solution and dried over magnesium sulfate to an oil. The oil isdissolved in ether, filtered through celite, and treated with etherealmaleic acid to form a salt. The salt is washed well with ether andrecrystallized from acetone-ether to give a white powder of3-(2,4-dichlorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate,m.p. 124°-127° C. A thrice recrystallized sample melts at 127°-129° C.

Analysis: Calculated for C₂₈ H₂₆ Cl₂ FNOS.C₄ H₄ O₄ : 60.96%C; 4.80%H;.2.22%N; 11.25%Cl. Found: 61.13%C; 4.78%H; 2.06%N; 11.02%Cl.

EXAMPLE 57

To 5.0 g of phenyl chloroformate in 80 ml of dichloromethane is added7.89 g of the free base,3-(3-fluorophenyl)-1,3-dihydro-1'-methylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 55, in 10 ml of dichloromethane over 20 minutes. The reactionmixture is stirred at room temperature for 21 hours, then diluted with200 ml of dichloromethane. The resultant mixture is washed with two 175ml portions of 10% aqueous sodium hydroxide solution, two 150 mlportions of water and one 70 ml portion of saturated aqueous sodiumchloride solution, and dried over magnesium sulfate to give an oil. Theoil is chromatographed on silica gel with dichloromethane to give anoil, which crystallizes to yield3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine],m.p. 134°-142° C. A portion is recrystallized twice from toluene:hexane,m.p. 144°-146° C.

Analysis: Calculated for C₂₅ H₂₂ FNO₂ S: 71.58%C; 5.29%H; 3.34%N. Found:71.60%C; 5.33%H; 3.22%N.

EXAMPLE 58

To 6.97 g of3-(3-fluorophenyl)-1,3-dihydro-1'-phenoxycarbonylspiro[benzo(c)thiophene-1,4'-piperidine]of Example 57 in 100 ml of ethylene glycol, under nitrogen, at 150° C.is added 16 g of 85% potassium hydroxide pellets. The reaction isstirred in a 160° C. bath for 45 minutes. The solution is then pouredinto 225 ml of ice-water, diluted to 500 ml and extracted with three 175ml portions of dichloromethane. The combined dichloromethane extractsare washed with 200 ml portions of water and one 50 ml portion ofsaturated aqueous sodium chloride solution, and dried over magnesiumsulfate to give a solid free base. The free base in ether is treatedwith ethereal maleic acid to give a salt. The salt is washed with etherand recrystallized from methanol-acetone-ether to give a white powder of3-(3-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleate,m.p. 188°-188.5° C.

Analysis: Calculated for: C₁₈ H₁₈ FNS: 63.61%C; 5.34%H; 3.37%N; 4.57%F.Found: 63.53%C; 5.37%H; 3.31%N; 4.45%F.

EXAMPLE 59

To 2.75 g (9.19 mmols) of free base3-(3-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]of Example 58 in 47 ml of sieve-dried dimethylformamide is added 2.81 gof γ-chloro-p-fluorobutyrophenone ethylene ketal with 1.82 g ofpotassium iodide and 1.82 g of sodium bicarbonate. The reaction isstirred at 65°-90° C. for 20 hours; then diluted with 75 ml ofchloroform, filtered, and rotary evaporated at 75° C. to an oil. The oilis partitioned between 125 ml of dichloromethane and 85 ml of water. A10 ml portion of saturated aqueous sodium bicarbonate is added and thesolutions separated. The organic layer is washed with one 80 ml portionof water and one 30 ml portion of saturated aqueous sodium chloridesolution and dried over magnesium sulfate to an oil. The oil ischromatographed on alumina with ether to give3-(3-fluorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal. Recrystallization from cyclohexane-pentane yields a sample whichmelts at 121.5°-123° C.

Analysis: Calculated for C₃₀ H₃₁ F₂ NO₂ S: 70.98%C; 6.17%H; 2.76%N.Found: 70.97%C; 6.20%H; 2.43%N.

EXAMPLE 60

To 3.75 g of3-(3-fluorophenyl)-1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 59 in 38 ml of ethanol is added 38 ml of 3Nhydrochloric acid. The reaction is refluxed for two hours and allowed tostand at room temperature for 16 hours. The solution is diluted with 100ml of water and a few ml of 40% aqueous sodium hydroxide solution areadded to achieve a pH of 11. The mixture is then diluted with 175 ml ofwater are extracted with three 175 ml portions of dichloromethanesolution. The combined dichloromethane extract is washed with two 125 mlportions of water and one 60 ml portion of saturated aqueous sodiumchloride solution and dried over magnesium sulfate to an oil. The oil,in ether, is treated with ethereal maleic acid; and the resulting saltwashed with ether and recrystallized from acetone ether to a white,crystalline powder of1'-[3-(4-fluorobenzoyl)propyl]-3-(3-fluorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]maleatem.p. 149°-150.5° C.

Analysis: Calculated for C₂₈ H₂₇ F₂ NOS.C₄ H₄ O₄ : 66.31%C; 5.39%H;2.42%N; 6.56%F. Found: 66.35%C; 5.54%H; 2.14%N, 6.61%F.

EXAMPLE 61

To a solution of 3.10 g of the free base1,3-dihydro-3-(4-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]of Example 40 in 54 ml of dimethylformamide is added 3.21 g of theγ-chloro-p-fluorobutyrophenone ethylene ketal, 2.07 g of potassiumiodide and 2.07 g of sodium bicarbonate. The reaction mixture is stirredand heated at 65°-90° C. 18 hours. The reaction mixture is diluted with75 ml of chloroform, filtered, and evaporated to an oil. The oil ispartitioned between 150 ml of dichloromethane and 125 ml of water. Theorganic layer is washed with water and an aqueous sodium chloridesolution and then dried over MgSO₄. The solution is filtered andevaporated to an oil which is column chromatographed on an Al₂ O₃ /Et₂O. A sample of the resultant free base is converted to the oxalate saltof1'-[3-(4-fluorobenzoyl)propyl]-3-(4-methylphenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal oxalate.

Analysis: Calculated for C₃₁ H₃₄ FNO₂ S.C₂ H₂ O₄ : 66.76%C; 6.11%H;2.36%N. Found: 66.85%C; 6.12%H; 2.32%N.

EXAMPLE 62

A solution of 2.57 g of1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(4-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 61, 27 ml of absolute ethanol, and 27 ml of 3N HCl isheated on a steam bath for 45 minutes. The reaction is cooled, dilutedwith 75 ml of water, and taken to pH 11 using a 40% aqueous NaOHsolution. The solution is diluted with 150 ml of water and extractedwith dichloromethane. The CH₂ Cl₂ fractions are combined, washed withwater and brine, and dried over MgSO₄. The dried CH₂ Cl₂ solution isfiltered and evaporated to an oil which solidifies under pentane. Thefiltered product is recrystallized from ethyl acetate to give1'-[3-(4-fluorobenzoyl)propyl]-1,3-dihydro-3-(4-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine],m.p. 134°-135° C.

Analysis: Calculated for C₂₉ H₃₀ FNOS: 75.78%C; 6.58%H; 3.05%N. Found:75.61%C; 6.67%H; 3.07%N.

EXAMPLE 63

To 6.87 g of3-(4-chlorophenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]of Example 15 in a solution of 33 ml of 2-butanone with 33 ml ofdimethylformamide is added 6.04 g of γ-chloro-2,4-difluorobutyrophenoneethylene ketal followed by 6.5 g of sodium bicarbonate and 4.08 g ofpotassium iodide. The reaction is stirred at 75°-80° C. for 18 hours,then 400 ml of ice-water is added and the mixture extracted with three125 ml portions of ether. The combined ether extracts are washed withtwo 150 ml portions of water and one 30 ml portion of brine and driedover magnesium sulfate to yield an oil. The oil is chromatographed on300 ml of alumina with ether to give an oil which eventuallycrystallizes to a product. A portion of the product is diluted withether, treated with ethereal maleic acid to form the salt. The salt isrecrystallized once from methanol-ether and once from acetone-ethylacetate pentane to give3-(4-chlorophenyl)-1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal maleate, melting at 148°-149° C.

Analysis: Calculated for C₃₀ H₃₀ ClF₂ NO₂ S.C₄ H₄ O₄ : 62.05%C; 5.21%H;2.13%N. Found: 61.94%C; 5.01%H; 2.16%N.

EXAMPLE 64

To 8.21 g (15.15 mmols) of free base3-(4-chlorophenyl)-1-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 63 in 62 ml of warm 95% ethanol is added 31 ml of 3Nhydrochloric acid, slowly, to give a suspension. The reaction is stirredat room temperature for 3 hours and on a steam bath for 45 minutes. Thereaction is then diluted with 400 ml of water and basified with ammoniumhydroxide. The aqueous mixture is extracted with two 150 ml portions ofether and two 250 ml portions of 1:1, ether:toluene. Combined organiclayers are washed with water and saturated aqueous sodium chloridesolution and dried over magnesium sulfate to a brown oil. The oil ischromatographed on silica gel with ether to give a solid. A portion ofthe product is recrystallized thrice from ether-pentane to give3-(4-chlorophenyl)-1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine],melting at 98°-100° C.

Analysis: Calculated for C₂₈ H₂₆ ClF₂ NOS: 67.52%C; 5.26%H; 2.81%N.Found: 67.25%C; 5.49%H; 2.69%N.

EXAMPLE 65

A mixture of1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine] of Example4 (3.75 g), 3.7 g of γ-chloro-2,4-difluorobutyrophenone ethylene ketal,2.5 g of Kl, 4.0 g of sodium bicarbonate in a mixture of 20 ml DMF and20 ml of 2-butanone is refluxed for 3 hours. The cooled mixture isdiluted with water, extracted three times with ether and the washed,dried ether solution concentrated to an oily residue. The residual ispurified by passing through an alumina column. Elution with etheraffords the tertiary amine which is converted to a crystalline maleateof1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal maleate, m.p. 171°-172.5° C.

Analysis: Calculated for C₃₀ H₃₁ F₂ NO₂ S.C₄ H₄ O₄ : 65.47%C; 5.66%H;5.14%S. Found: 65.21%C; 5.68%H; 5.36%S.

EXAMPLE 66

A solution of 5.0 g of the free base1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 65 in 20 ml of 3N HCl and 20 ml of water is allowed tostand at room temperature for 3 hours. The excess acid and solvents areremoved under pressure at 60° C., the residue is basified withconcentrated NH₄ OH. The liberated oil is taken up in ether, washed anddried. Removal of solvents yields a clear oil which is converted to acrystalline maleate in ether of1'-[3-(2,4-difluorobenzoyl)propyl]-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine]maleate,m.p. 134°-135° C.

Analysis: Calculated for C₂₈ H₂₇ F₂ NOS.C₄ H₄ O₄ : 66.67%C; 5.39%H;5.53%S. Found: 66.21%C; 5.36%H; 5.79%S.

EXAMPLE 67

To 5.60 g of the free base1'-[3-(4-fluorobenzoyl)propyl]-3-(3-methylphenyl)-1,3-dihydrospiro[benzo(c)thiophene-1,4'-piperidine]ethyleneketal of Example 50 in 56 ml of warm ethanol is slowly added 56 ml of 3Nhydrochloric acid. The reaction is refluxed for 45 minutes, then cooledto room temperature, basified with a small amount of 40% aqueous sodiumhydroxide, and diluted with 350 ml of water. The solution is extractedwith three 150 ml portions of dichloromethane. The combineddichloromethane extract is washed with two 200 ml portions of water, one75 ml portion of brine and dried over magnesium sulfate to give an oil.The oil is dissolved in ether, filtered, and treated with etherealhydrogen bromide to form a salt. The salt is washed with ether andrecrystallized from methanol-acetone-ether to give a powder of1'-[3-(4-fluorobenzoyl)propyl-1,3-dihydro-3-(3-methylphenyl)spiro[benzo(c)thiophene-1,4'-piperidine]hydrobromidewhich shrinks to a gel at 190°-195° C. and melts to a dark fluid at217°-218° C.

Analysis: Calculated for C₂₉ H₃₀ FNOS.HBr: 64.44%C; 5.73%H; 2.59%N;3.52%F. Found: 64.30%C; 5.79%H; 2.48%N; 3.56%F

EXAMPLE 68 Physostigmine Lethality in Mice

Groups of ten male CD-1 mice (18-25 gms) are utilized for a TimeResponse. Animals received food and water ad libitum. Drugs are preparedin distilled water. If insoluble, one drop of a suitable surfactant isadded. Dose volume is 10 ml/kg.

The test compound is administered intraperitoneally (i.p.). Controlgroup receives vehicle. At 30, 60 and 120 minutes after administrationof test compound, an i.p. injection of physostigmine sulfate at 2.5ml/kg is given to each of the animals.

One hour after each physostigmine injection the groups are checked fordeaths. Surviving mice are considered protected. Of the three timeperiods checked, the time period with the greatest protection is thepeak time of drug activity. If there are animals protected in thevehicle control group, the normalized percent protected is calculatedthus: ##EQU1##

    ______________________________________                                        RESULTS                                                                                                    Anticholinergic                                                               Activity                                                             Dose     Normalized                                                           (mg/kg,  % Protected                                      Compound            i.p.)    at Peak Time                                     ______________________________________                                        1,3-dihydro-3-(4-tolyl)spiro[iso-                                                                 50       83                                               benzofuran-1,4'piperidine]                                                                        50       50                                                                   64       10                                                                   32       10                                                                   16       10                                                                   8        30                                               1,3-dihydro-3-(4-tolyl)spiro[benzo-                                                               50       40                                               (c)thiophene-1,4'-piperidine]                                                 1,3-dihydro-1'methyl-3-(2-tolyl)-                                                                 50       33                                               spiro[isobenzofuran-1,4'piperidine]                                           1,3-dihydro-1'-methyl-3-(2-tolyl)-                                                                50       0                                                spiro[benzo(c)thiophene-1,4'-                                                 piperidine]                                                                   1,3-dihydro-3-phenylspiro[iso-                                                                    25       44                                               benzofuran-1,4'-piperidine]                                                                       10       44                                               1,3-dihydro-3-phenylspiro[benzo-                                                                  50       10                                               (c)thiophene-1,4'piperidine]                                                                      10       0                                                1,3-dihydro-3-(4-fluorophenyl)spiro-                                                              25       63                                               [isobenzofuran-1,4'-piperidine]                                                                   10       63                                               1,3-dihydro-3-(4-fluorophenyl)spiro-                                                              40       0                                                [benzo(c)thiophene-1,4'-                                                      piperidine]                                                                   1,3-dihydro-1'-[3-(4-fluoro-                                                                      25       0                                                benzoyl)propyl]-3-(4-fluoro-                                                  phenyl)-spirol[isobenzofuran-                                                 1,4'-piperidine]                                                              1,3-dihydro-1'-[3-(4-fluoro-                                                                      50       0                                                benzoyl)-propyl]-3-(4-fluoro-                                                 phenyl)spiro[benzo(c)thiophene-                                               1,4'-piperidine]                                                              1,3-dihydro-1'-[3-(4-fluoro-                                                                      50       20                                               benzoyl)propyl]-3-(4-methyl-                                                  phenyl)spiro[isobenzofuran-                                                   1,4'-piperidine]                                                              1,3-dihydro-1'-[3-(4-fluoro-                                                                      64       10                                               benzoyl)propyl]spiro[isobenzo-                                                furan-1,4'-piperidine]                                                        1,3-dihydro-1'-[3-(4-fluoro-                                                                      25       10                                               benzoyl)propyl]-5-methoxy-                                                    spiro[isobenzofuran-1,4'-                                                     piperidine]                                                                   1,3-dihydro-3-(4-chlorophenyl)-                                                                   25       0                                                1'-[3-(4-fluorobenzoyl)propyl]-                                               spiro[isobenzofuran-1,4'-                                                     piperidine]                                                                   1,3-dihydro-6-fluoro-1'-                                                                          25       0                                                [3-(4-fluorobenzoyl)propyl]-                                                  spiro[isobenzofuran-1,4'-                                                     piperidine]                                                                   1,3-dihydro-3-(2-methylphenyl)-                                                                   50       0                                                spiro[isobenzofuran-1,4'-                                                     piperidine]                                                                   1,3-dihydro-6-chloro-1'-[3-                                                                       25       0                                                (4-fluorobenzoyl)propyl]spiro-                                                [isobenzofuran-1,4'-piperidine]                                               1,3-dihydro-3-(4-fluorophenyl)-                                                                   50       78                                               1'-methylspiro[benzo(c)thio-                                                                      40       17                                               phene-1,4'-piperidine]                                                                            64       0                                                                    32       0                                                1,3-dihydro-3-(4-chlorophenyl)-                                                                   50       0                                                spiro[benzo(c)thiophene-1,4'-                                                 piperidine]                                                                   1,3-dihydro-3-(4-chlorophenyl)-1'-                                                                50       0                                                methylspiro[benzo(c)thiophene-1,4'-                                           piperidine]                                                                   1,3-dihydro-3-(3,4-dichloro-                                                                      50       0                                                phenyl)-spiro[benzo(c)thio-                                                   phene-1,4-piperidine]                                                         1,3-dihydro-3-(2,4-dichloro-                                                                      50       0                                                phenyl)-1'-methylspiro(benzo-                                                 (c)thiophene-1,4'-piperidine]                                                 1,3-dihydro-3-(3,4-dichlorophenyl)                                                                50       0                                                1'-methylspiro[benzo(c)thiophene-                                             1,4'-piperidine]                                                              1,3-dihydro-3-(4-chlorophenyl)-1'-                                                                50       17                                               (cyclopropylmethyl)-spiro-[benzo(c)-                                          thiophene-1,4'-piperidine]                                                    1,3-dihydro-1'-methyl-3-phenyl-                                                                   25       0                                                [benzo(c)thiophene-1,4'-piperidine]                                           1,3-dihydro-3-(4-methylphenyl)-                                                                   50       40                                               1'-methyl-spiro[benzo(c)-                                                     thiophene-1,4'-piperidine]                                                    1,3-dihydro-3-(3-methylphenyl)-                                                                   50       0                                                spiro[benzo(c)thiophene-1,4'-                                                 piperidine]                                                                   ______________________________________                                    

We claim:
 1. A process for preparing a compound of the formula ##STR19##or an optical antipode or pharmaceutically acceptable salt thereof inwhich R is loweralkyl or phenylloweralkyl, R¹ and R² are the same ordifferent and each can be hydrogen, loweralkyl, loweralkoxy,trifluoromethyl, chlorine, bromine, fluorine, methylenedioxy orloweralkylthio and m, n and n' are integers from 1 to 3; and the sum ofn and n' is 3 or 4 which comprises converting a 2-bromo-fluorobenzene ofthe formula ##STR20## to its 2-lithio derivatives with aloweralkyllithium at a temperature ranging from -80° to -20° C., in asuitable solvent such as ether, hexane or tetrahydrofuran, reacting the2-lithio derivative with a cycloazalkanone of the formula ##STR21## inwhich R is loweralkyl or phenylloweralkyl to provide aphenylcycloazalkanol of the formula ##STR22## reacting thephenylcycloazalkanol with a benzylmercaptan of the formula ##STR23## inthe presence of glacial acetic acid and boron trifluoride etherate at atemperature of from ambient to 100° C. to provide a4-benzylthio-4-phenylcycloazalkane of the formula ##STR24## andcyclizing the 4-benzylthio-4-phenylcycloazalkane.